DESCRIPTION: Malignant human gliomas constitute a group of highly lethal neoplasms. Chloroethylnitrosoureas (CENUs) are moderately effective in the treatment of gliomas in adults. They produce cytotoxicity by alkyl substitution of DNA guanine residues, with subsequent formation of DNA intrastrand cross-links. The alkyl group can be removed from the O6 position by a DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGAT), with restoration of an intact guanine. Resistance and susceptibility to nitrosoureas and methylating agents such as procarbazine can be mediated by this protein, which is expressed in the majority of tumors studied to date, including those arising in the central nervous system. The observation that depletion of AGAT with alkylguanines or methylating agents sensitizes cells to the cytotoxic action of CENUs provides the opportunity for the use of combination therapy designed to restore sensitivity to tumor cells resistant to the CENU carmustine (BCNU). Recent studies have demonstrated enhancement of nitrosourea activity in human medulloblastoma and glioblastoma multiforme xenografts growing subcutaneously and intracranially in athymic nude mice by O6-benzylguanine-mediated depletion of AGAT. The hypotheses of this project are: 1) High grade glioma AGAT levels and cellular distribution determine response to nitrosoureas and 2) inhibition of AGAT activity by O6- benzylguanine can reverse nitrosourea resistance in high grade gliomas without an unacceptable increase in toxicity. The specific aims of the project are: 1) To define the optimal doses of the combination of O6-benzylguanine and BCNU in the treatment of patients with recurrent anaplastic astrocytoma or glioblastoma multiforme and 2) To define the activity of the combination of O6-benzylguanine and BCNU in the treatment of patients with recurrent anaplastic astrocytoma or glioblastoma multiforme.